Gel dosimeter for measuring radiation dose

ABSTRACT

A gel dosimeter for radiation dosimetry includes a radically polymerizable monomer, a gelator, glucose, and glucose oxidase. Although a conventional polymer gel dosimeter contains a deoxygenating agent such as tetrakis(hydroxymethyl)phosphonium chloride, such a deoxygenating agent fails to exhibit sufficient effects. Thus, a more effective deoxygenation treatment technique has been required for a gel dosimeter.

TECHNICAL FIELD

The present invention relates to a gel dosimeter used for a radiationdosimeter. More particularly, the present invention relates to a polymergel dosimeter for radiation dosimetry to verify a three-dimensional dosedistribution in a radiation therapy regimen for cancer, etc.

BACKGROUND ART

Radiation therapies for cancer that have been introduced includehigh-precision therapies, such as stereotactic radiation therapy (SRT);i.e., pinpoint radiation therapy, and intensity modulated particletherapy (IMPT), which can achieve three-dimensional setting of anirradiation field along the contour of a cancer by changing a doseintensity in the same irradiation field. In such a therapy, theintegrated value (i.e., dose distribution) of the amount of microscopicenergy applied to each three-dimensional position of the target isprecisely adjusted. A particle beam therapy has also been performed,which utilizes charged particle beams with high dose concentration, suchas proton beams or heavy particle beams (e.g., carbon beams or neonbeams). The particle beam therapy is advantageous in that a tumor can betreated through control of the position of radiation exposure and thedose of radiation with higher precision than a conventional X-raytherapy. The particle beam therapy is required to properly releaseenergy from particle beams at the position of a target (e.g., a lesionin a living tissue) and also to have as little effect as possible on anormal tissue around the target. For these purposes, the radial spreadof particle beams and the position of the Bragg peaks of particle beamsare controlled with respect to the target position in the irradiatedbody.

In a practical radiation therapy regimen, the dose distribution isoptimized at each three-dimensional position in a living tissue. In atypical therapy regimen, the dose distribution (radiation doses to eachposition) in the target tissue is varied in accordance with the purposeof the therapy, as well as the influence of the radiation on thesurrounding normal tissues is reduced, and the influence of theradiation on an organ at risk is also reduced to a minimum possiblelevel. In order to achieve such a complicated-shaped dose distribution,beams may be precisely controlled and irradiated from multipledirections. This control is performed with a filter or a collimator(e.g., a range shifter, a multi-leaf collimator, or a bolus) that isadjusted in accordance with the irradiated body. In order to realizehighly controlled radiation therapy, advanced quality assurance andquality control (hereinafter abbreviated as “QA/QC”) are required forthe entire device including a radiation exposure device, an auxiliary, afilter, a collimator, etc., and for the irradiation process by such adevice.

Such a therapy regimen and the QA/QC of various devices require atechnique capable of appropriately integrating and actually measuringthe amount of energy applied by a large amount of ionizing radiationsincident from different directions at various acceleration energies.This is because, if the amount of energy applied can be integrated andthe dose can be measured precisely at each position, thethree-dimensional distribution of the amount of energy applied (dosedistribution), which supports the aforementioned QA/QC, can be measured.For this purpose, a one-dimensional, two-dimensional, or pseudothree-dimensional (placement of a detector on an orthogonal plane or acylinder) dosimeter, such as an ionization chamber dosimeter, a film, ora semiconductor detector, has conventionally been used. In such adosimeter, the aforementioned dose distribution with respect toone-dimensional or two-dimensional coordinates is actually measured inthe region where particle beams are aligned with the target position. Inrecent years, besides these dosimeters, attention has been paid to a geldosimeter capable of measuring a three-dimensional dose distributionwith use of the measurement principle of a chemical dosimeter. The useof a gel dosimeter is advantageous in that the amount of energy appliedby radiation at each position of water (i.e., a material that can beregarded as equivalent to a living organism) can be accurately measured;i.e., the influence of radiation can be measured in a bioequivalentsubstance or a water-equivalent substance. The gel dosimeter can acquirea three-dimensional dose distribution while the dosimeter itself is usedas a solid phantom.

Hitherto reported gel dosimeters capable of measuring athree-dimensional dose distribution include a Fricke gel dosimeter(Patent Document 1), a polymer gel dosimeter (Patent Documents 2 and 3),and a dye gel dosimeter. A Fricke gel dosimeter is composed of a gelcontaining a solution (an aqueous solution containing ferrous sulfate)of a Fricke dosimeter known as a liquid chemical dosimeter, and utilizesabsorbed-dose-proportional enhancement of oxidation reaction (fromdivalent to trivalent) of iron (coloring) in association with radiationexposure. Meanwhile, a polymer gel dosimeter is prepared by dispersionof a monomer in a gel. In the polymer gel dosimeter, a polymer is formedin a dose-proportional manner upon radiation exposure, and therelaxation time of water changes in the irradiated portion. Thus, thedose can be estimated through reading by MRI (magnetic resonanceimaging). Also, portions that have become clouded by radiation exposurecan be detected with an optical CT device. The polymer produced byradiation exposure is less likely to be diffused in the gel, andclouding is stable over time. In addition, the clouded portions seem tofloat in the transparent gel. Therefore, the polymer gel dosimeter ischaracterized by its superior visuality.

Hydrogels produced by using glucose and glucose oxidase as deoxygenatingagents have been reported (Non-Patent Document 1).

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: JP 2014-209093 A-   Patent Document 2: JP 5590526 B-   Patent Document 3: JP 2014-185969 A

Non-Patent Documents

-   Non-Patent Document 1: Nature Materials (2016), 15, 413-418

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

A conventional polymer gel dosimeter contains a water-solublepolymerizable monomer such as methacrylic acid or acrylamide. Since thepolymerization reaction of such a polymerizable monomer is inhibited bythe presence of oxygen (O₂) in the reactant, the reaction generallyinvolves deoxygenation treatment. Although a conventional polymer geldosimeter contains a deoxygenating agent such astetrakis(hydroxymethyl)phosphonium chloride, sodium ascorbate, or coppersulfate, such a deoxygenating agent fails to exhibit sufficient effects.Thus, a more effective deoxygenation treatment technique has beenrequired for a polymer gel dosimeter.

A polymer gel dosimeter is read by MRI after radiation exposure.Although radiation exposure and MRI are performed at room temperature, aconventional gel dosimeter must be stored in a refrigerator when it isnot subjected to these operations. Thus, a conventional gel dosimeterposes a problem that it cannot be stored at room temperature. Hydrogelis a material that can be used as a refrigerant, and it takes severalhours to one night for bringing it back to room temperature from arefrigerated state. Thus, hydrogel faces a problem that, for example, itmust be taken out of a refrigerator the day before use.

Means for Solving the Problems

The present inventors have conducted extensive studies on an effectivedeoxygenation treatment for a gel dosimeter, and as a result have foundthat the deoxygenation can be performed by a method involving theaddition of glucose and glucose oxidase. The present invention has beenaccomplished on the basis of this finding.

Accordingly, a first aspect of the present invention is a gel dosimeterfor radiation dosimetry comprising a radically polymerizable monomer, agelator, glucose, and glucose oxidase.

A second aspect of the present invention is the gel dosimeter forradiation dosimetry according to the first aspect, wherein the gelatoris one or more selected from the group consisting of gelatin, agarose,xanthan gum, carrageenan, gellan gum, chitosan, and alginic acid, andsodium, potassium, magnesium, and calcium salts thereof, includingpartially neutralized products thereof.

A third aspect of the present invention is the gel dosimeter forradiation dosimetry according to the first aspect, wherein the gelatorcontains polyvinyl alcohol and glutaraldehyde or borax.

A fourth aspect of the present invention is the gel dosimeter forradiation dosimetry according to the first aspect, wherein the gelatorcontains a water-soluble organic polymer (A) having an organic acidstructure, an organic acid salt structure, or an organic acid anionstructure, a silicate salt (B), and a dispersant (C) for the silicatesalt.

A fifth aspect of the present invention is the gel dosimeter forradiation dosimetry according to the fourth aspect, wherein thewater-soluble organic polymer (A) is a completely neutralized orpartially neutralized polyacrylic acid salt having a weight averagemolecular weight of 1,000,000 to 10,000,000, or a mixture thereof.

A sixth aspect of the present invention is the gel dosimeter forradiation dosimetry according to the fourth or fifth aspect, wherein thesilicate salt (B) is one or more water-swellable silicate salts selectedfrom the group consisting of smectite, bentonite, vermiculite, and mica.

A seventh aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the fourth to sixth aspects,wherein the dispersant (C) is one or more selected from the groupconsisting of sodium orthophosphate, sodium pyrophosphate, sodiumtripolyphosphate, sodium tetraphosphate, sodium hexametaphosphate,sodium polyphosphate, sodium etidronate, sodium poly(meth)acrylate,ammonium poly(meth)acrylate, a sodium acrylate/sodium maleate copolymer,an ammonium acrylate/ammonium maleate copolymer, sodium hydroxide,hydroxylamine, sodium carbonate, sodium silicate, polyethylene glycol,polypropylene glycol, sodium humate, sodium ligninsulfonate, andpotassium salts corresponding to these salts.

An eighth aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the first to seventhaspects, wherein the radically polymerizable monomer is a water-solublepolymerizable monomer.

A ninth aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the first to eighth aspects,wherein the gel dosimeter further comprises a water-solublepolyfunctional acrylamide monomer as a crosslinking agent.

A tenth aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the first to ninth aspects,wherein the gel dosimeter further comprises water-dispersible inorganicmicroparticles as a sensitizer.

An eleventh aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the first to tenth aspects,wherein the gel dosimeter further comprises, as a stabilizer, apolymerization inhibitor, a radical scavenger, or an antioxidant.

A twelfth aspect of the present invention is the gel dosimeter forradiation dosimetry according to any one of the first to eleventhaspects, wherein the gel dosimeter further comprises a buffer.

A thirteenth aspect of the present invention is the gel dosimeter forradiation dosimetry according to the twelfth aspect, wherein the bufferis one or more selected from the group consisting of phosphoric acid,citric acid, acetic acid, boric acid, tartaric acid, salts of these,Tris, and HEPES.

Effects of the Invention

The gel dosimeter of the present invention prepared throughdeoxygenation treatment exhibits an excellent deoxygenation effect, ascompared with a deoxygenating agent widely used in conventional geldosimeters, such as tetrakis(hydroxymethyl)phosphonium chloride, sodiumascorbate, or copper sulfate.

The gel dosimeter of the present invention prepared throughdeoxygenation treatment may involve the use of various gelators,including widely used gelatin or agarose, a water-soluble organicpolymer, a hydrogel containing a silicate salt and a dispersant for thesilicate salt, and a hydrogel containing polyvinyl alcohol andglutaraldehyde or borax.

The gel dosimeter of the present invention prepared throughdeoxygenation treatment can be stored at room temperature without theneed for refrigerated storage before and after a polymerization reactionunlike conventional cases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the correlation between ΔR₂ and irradiatedX-ray dose in Examples 1 and 2.

FIG. 2 shows the state of a dosimeter after X-ray irradiation in Example1; i.e., the state after irradiation of 0, 0.5, 1, 3, 5, and 7 Gy (fromleft to right).

FIG. 3 shows the state of a dosimeter after X-ray irradiation in Example2; i.e., the state after irradiation of 0, 0.5, 1, 3, 5, and 7 Gy (fromleft to right).

FIG. 4 is a graph showing the correlation between ΔR₂ and irradiatedX-ray dose in Example 3 after one day and after two weeks.

FIG. 5 is a graph showing the correlation between ΔR₂ and irradiatedX-ray dose in Comparative Example 1 after one day and after two weeks.

MODES FOR CARRYING OUT THE INVENTION

The gel dosimeter of the present invention contains, as components, adeoxygenating agent, a gelator, a crosslinking agent, and a radicallypolymerizable monomer. If necessary, the gel dosimeter may contain,besides the aforementioned components, an additional component such as asensitizer or stabilizer, so long as the intended effects of the presentinvention are not impaired.

[Deoxygenating Agent]

The deoxygenating agent may be a combination of glucose and glucoseoxidase. The amount of glucose is 0.01% by mass to 10% by mass,preferably 0.1% by mass to 5% by mass, more preferably 0.5% by mass to3% by mass, relative to 100% by mass of the gel dosimeter. The titer ofglucose oxidase is 10 units/g to 1,000,000 units/g, preferably 100units/g to 500,000 units/g, more preferably 1,000 units/g to 300,000units/g, wherein 1 unit corresponds to the amount required for oxidizing1.0 μmol of β-D-glucose into D-gluconolactone and hydrogen peroxidewithin one minute at 25° C. and pH 7.0. The amount of glucose oxidase is0.1 ppm to 10,000 ppm, preferably 0.5 ppm to 5,000 ppm, more preferably1 ppm to 1,000 ppm, relative to 100% by mass of the gel dosimeter.Catalase may also be added to decompose hydrogen peroxide generatedduring glucose oxidation. The optimal pH for glucose oxidase is 5 to 7,and a buffer may be added if desired. Examples of the buffer includephosphoric acid, citric acid, acetic acid, boric acid, tartaric acid,salts of these, Tris, and HEPES.

[Gelator]

The gelator used may be one which gelates at room temperature, is atsuch a level that it can be used in a gel dosimeter, and does notinhibit the radical polymerization of a radically polymerizable monomerby radiation exposure. A gelator used in a polymer gel dosimeter may beused.

Examples of the gelator include gelatin, agarose, xanthan gum,carrageenan, gellan gum, chitosan, and alginic acid, which are naturalpolymers derived from animals and plants, and sodium, potassium,magnesium, and calcium salts thereof, including partially neutralizedproducts thereof; a gel-forming composition containing a water-solubleorganic polymer (A) having an organic acid structure, an organic acidsalt structure, or an organic acid anion structure, a silicate salt (B),and a dispersant (C) for the silicate salt; and a gel-formingcomposition containing polyvinyl alcohol and glutaraldehyde or borax.

The amount of the natural polymer is 0.01% by mass to 30% by mass,preferably by mass to 20% by mass, relative to 100% by mass of the geldosimeter.

Examples of the water-soluble organic polymer (A) having an organic acidsalt structure or an organic acid anion structure include water-solubleorganic polymers having a salt structure or anion structure of anorganic acid group such as a carboxyl group, a sulfonyl group, or aphosphonyl group.

Examples of the water-soluble organic polymer include those having acarboxyl group, such as salts of poly(meth)acrylic acid, carboxyvinylpolymer, and carboxymethylcellulose; those having a sulfonyl group, suchas salts of polystyrene sulfonic acid; and those having a phosphonylgroup, such as polyvinyl phosphonates. Preferred is a salt ofpolyacrylic acid.

The water-soluble organic polymer (A) has a weight average molecularweight of preferably 1,000,000 or more and 10,000,000 or less, forexample, 2,500,000 or more and or less.

The water-soluble organic polymer (A) preferably has a linear-chainstructure and has neither a branched structure nor a chemicallycrosslinked structure.

The water-soluble organic polymer (A) having an organic acid structuremay be a completely neutralized or partially neutralized polymer havingan organic acid group.

Examples of the organic acid salt structure include sodium salts,ammonium salts, potassium salts, and lithium salts of organic acidgroups.

Examples of the organic acid anion structure include structures formedby dissociation of cations from organic acid groups or organic acidsalts.

The water-soluble organic polymer (A) may be, for example, a completelyneutralized or partially neutralized organic polymer having an organicacid group, or a mixture of such polymers.

The water-soluble organic polymer (A) is, for example, completelyneutralized or partially neutralized linear-chain sodium polyacrylate.

The amount of the aforementioned water-soluble organic polymer (A) is0.01% by mass to 20% by mass, preferably 0.05% by mass to 10% by mass,relative to 100% by mass of the gel dosimeter.

Examples of the aforementioned silicate salt (B) include particles ofwater-swellable silicate salts, such as smectite, bentonite,vermiculite, and mica. The silicate salt (B) preferably forms a colloidwith water or a water-containing liquid serving as a dispersion medium.

Primary particles of the silicate salt are in, for example, a disc-like,plate-like, spherical, particulate, cubic, acicular, rod-like, oramorphous form. For example, the silicate salt is preferably in the formof disk-like or plate-like particles having a diameter of 5 nm to 1,000nm. Specific examples of the silicate salt include layered silicatesalts. Examples of readily available commercial products includeLAPONITE XLG (synthetic hectorite), LAPONITE XLS (synthetic hectoritecontaining sodium pyrophosphate as a dispersant), LAPONITE XL21 (sodiummagnesium fluorosilicate), LAPONITE RD (synthetic hectorite), LAPONITERDS (synthetic hectorite containing an inorganic polyphosphate salt as adispersant), and LAPONITE 5482 (synthetic hectorite containing sodiumetidronate as a dispersant) available from BYK Additives & Instruments;KUNIPIA (montmorillonite), SUMECTON SA (synthetic saponite), SUMECTON ST(synthetic saponite), SUMECTON SWN (synthetic smectite), and SUMECTONSWF (synthetic smectite) available from Kunimine Industries Co., Ltd.;and BEN-GEL (purified product of natural bentonite) available from HOJUNCo., Ltd.

The amount of the aforementioned silicate salt (B) is 0.01% by mass to20% by mass, preferably 0.05% by mass to 10% by mass, relative to 100%by mass of the gel dosimeter.

The dispersant (C) for the silicate salt may be a dispersant ordeflocculant used for the purpose of improvement of the dispersibilityof a silicate salt or exfoliation of a layered silicate salt. Thedispersant (C) may be, for example, a phosphate salt dispersant, acarboxylate salt dispersant, a dispersant acting as an alkali, or anorganic deflocculant.

Examples of the phosphate salt dispersant include sodium orthophosphate,sodium pyrophosphate, sodium tripolyphosphate, sodium tetraphosphate,sodium hexametaphosphate, sodium polyphosphate, and sodium etidronate.Examples of the carboxylate salt dispersant include sodiumpoly(meth)acrylate, ammonium poly(meth)acrylate, sodium acrylate/sodiummaleate copolymers, and ammonium acrylate/ammonium maleate copolymers.Examples of the dispersant acting as an alkali include sodium hydroxideand hydroxylamine. Examples of the dispersant that reacts with apolyvalent cation to form an insoluble salt or a complex salt includesodium carbonate and sodium silicate. Examples of the organicdeflocculant include polyethylene glycol, polypropylene glycol, sodiumhumate, and sodium ligninsulfonate. Other examples include phosphatesalt dispersants such as potassium salts. Preferably, the phosphate saltdispersant is sodium pyrophosphate; the carboxylate salt dispersant islow-polymerization sodium polyacrylate having a weight average molecularweight of 1,000 to 20,000; and the organic deflocculant is polyethyleneglycol (e.g., PEG 900).

The low-polymerization sodium polyacrylate is known to act as adispersant through, for example, a mechanism by which thelow-polymerization sodium polyacrylate interacts with silicate saltparticles to generate carboxy anion-derived negative charges on thesurfaces of the particles, to thereby disperse the silicate salt bycharge repulsion.

The amount of the dispersant (C) is 0.01% by mass to 20% by mass,preferably by mass to 10% by mass, more preferably 0.5% by mass to 5% bymass, relative to 100% by mass of the gel dosimeter.

When the silicate salt used is in the form of a product containing adispersant, the dispersant is not necessarily further added.

As described above, one example of the gelator is a gel-formingcomposition containing polyvinyl alcohol and glutaraldehyde or borax.The polyvinyl alcohol has a degree of polymerization of 10 to 8,000,preferably 100 to 5,000, more preferably 500 to 3,000, and a degree ofsaponification of 80% to 99%, preferably 88% to 99%.

[Crosslinking Agent]

The crosslinking agent is preferably a water-soluble polyfunctionalacrylamide monomer, in particular, N,N′-methylenebisacrylamide, FAM-301,FAM-401, and FOM-03006 (available from FUJIFILM Wako Pure ChemicalCorporation). The amount of the crosslinking agent is 0.01% by mass to20% by mass, preferably 0.1% by mass to 10% by mass, more preferably0.5% by mass to 5% by mass, relative to 100% by mass of the geldosimeter.

[Radically Polymerizable Monomer]

The gel dosimeter for radiation dosimetry of the present invention maycontain a radically polymerizable monomer utilizing a mechanism by whichradicals are generated in the monomer through radiation exposure, andthe degree of polymerization through reaction caused by the radicalscorresponds to the dose. Thus, the gel dosimeter of the presentinvention contains a radiation dosimetry gel as a material for radiationdosimetry.

[Water-Soluble Polymerizable Monomer]

The aforementioned radically polymerizable monomer may be awater-soluble polymerizable monomer.

Examples of the water-soluble polymerizable monomer include compoundshaving an acrylic structure or a vinyl structure.

Examples of the water-soluble polymerizable monomer include(meth)acrylic acid, (meth)acrylamide, hydroxyethyl (meth)acrylate,N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide,4-(meth)acryloylmorpholine, N-vinylpyrrolidone, and N-vinylacetamide.The aforementioned water-soluble polymerizable monomers may be usedalone or in combination of two or more species. The amount of thewater-soluble polymerizable monomer is 0.01% by mass to 30% by mass,preferably 0.1% by mass to 20% by mass, more preferably 0.5% by mass to15% by mass, relative to 100% by mass of the gel dosimeter.

[Sensitizer]

The gel dosimeter may contain a magnesium salt or water-dispersibleinorganic microparticles having the effect of enhancing radiationsensitivity. The enhancement of radiation sensitivity by a magnesiumsalt is disclosed in the literature (Radiological Physics and Technology(2018) 11: 375-381). Examples of the magnesium salt include magnesiumchloride and magnesium sulfate. The amount of the magnesium salt is 0.1%by mass to 50% by mass, preferably 0.5% by mass to 25% by mass, morepreferably 1% by mass to 10% by mass, relative to 100% by mass of thegel dosimeter. Examples of the water-dispersible inorganicmicroparticles include silica sol, alumina sol, and zirconia sol.Examples of readily available commercial products include SNOWTEX(silica sol, available from Nissan Chemical Corporation), SILICADOL(silica sol, available from NIPPON CHEMICAL INDUSTRIAL CO., LTD.), andQuartron (silica sol, available from FUSO CHEMICAL CO., LTD.). Theamount of the water-dispersible inorganic microparticles is 0.01% bymass to 50% by mass, preferably 0.05% by mass to 10% by mass, morepreferably 0.1% by mass to 5% by mass, relative to 100% by mass of thegel dosimeter.

[Stabilizer]

The gel dosimeter may contain a stabilizer for preventing deteriorationor deactivation of the dosimeter before radiation exposure. Examples ofthe stabilizer include a polymerization inhibitor, a radical scavenger,and an antioxidant, such as hydroquinone, 4-methoxyphenol, andN,N′-diisobutyl-p-phenylenediamine. The amount of the stabilizer is 0.1ppm to 10,000 ppm, preferably 1 ppm to 5,000 ppm, more preferably 10 ppmto 3,000 ppm, relative to 100% by mass of the gel dosimeter.

[Production Method for Gel Dosimeter and Gel (Gelator)]

No particular limitation is imposed on the production methods for thegel dosimeter and gel of the present invention. For example, ahomogeneous solution or a transparent dispersion may be prepared bymixing a monomer that can be polymerized through radiation exposure anda gelator in predetermined proportions, and mixing the resultant mixturewith a crosslinking agent, a sensitizer, and, if desired, an additionalcomponent such as a deoxygenating agent, a stabilizer, or a buffer.

Each component may be used after being dissolved or dispersed in asolvent as appropriate. No particular limitation is imposed on thesolvent, so long as it can dissolve or homogeneously disperse therespective components of the gel dosimeter. The solvent is preferablywater. Water may be mixed with an aqueous solvent such as methanol,ethanol, isopropanol, or glycerol.

When the gelator used is a gel-forming composition containing thecomponents (A) to (C), the gel dosimeter may be produced by thefollowing method. For example, two of the components (A) to (C) aremixed to thereby prepare a homogeneous solution, and then the remainingcomponent and a monomer are added to the solution. Thereafter, theresultant mixture is mixed with a crosslinking agent, a sensitizer, and,if desired, an additional component such as a deoxygenating agent or astabilizer, to thereby prepare a homogeneous solution.

Alternatively, the gel dosimeter may be produced by the followingmethod. For example, an aqueous dispersion containing the components (B)and (C) and water is added to an aqueous solution containing thecomponent (A), a monomer that can be polymerized through radiationexposure, a crosslinking agent, a sensitizer, an additional component(if desired), and water, and the resultant mixture is heated asappropriate, to thereby prepare a homogeneous solution.

When the gelator used is a natural polymer derived from an animal or aplant, the gel dosimeter may be produced by the following method. Forexample, a monomer that can be polymerized through radiation exposure, anatural polymer, a crosslinking agent, a sensitizer, and an additionalcomponent (if desired) are added to water, and the resultant mixture isheated as appropriate, to thereby prepare a homogeneous solution.

Examples of the method for mixing the respective components includemechanical or manual stirring, ultrasonic stirring, and continuousmixing by line mixing. In particular, mechanical stirring and continuousmixing are preferred.

The mechanical stirring may be performed with, for example, a magneticstirrer, a propeller-type stirrer, a planetary centrifugal mixer, adisper, a homogenizer, a shaker, a vortex mixer, a ball mill, a kneader,or an ultrasonic oscillator. Of these, a planetary centrifugal mixer ispreferably used. The continuous mixing may be performed with, forexample, Line Mixer (available from Satake Multimix Corporation),In-Line Mixer (available from Silverson Nippon Limited), Vibro Mixer(available from REICA Co., Ltd.), Static Mixer (available from, forexample, Noritake Co., Limited, Japan Flow Controls, Co., Ltd., or SanyoSeiki Co., Ltd.), Spiral Mixer (available from Japan Flow Controls, Co.,Ltd.), FlowMix (available from Mountech Co., Ltd.), or Square Mixer(available from Sakura Seisakusho Ltd.). Of these, Static Mixer ispreferably used.

The temperature during mixing is, for example, the freezing point to theboiling point of the aqueous solution or the aqueous dispersion,preferably −5° C. to 100° C., more preferably 0° C. to 50° C.

Although the mixture has low strength and is in the form of solimmediately after completion of the mixing, the mixture gelates afterbeing allowed to stand still. The mixture is preferably allowed to standstill for two hours to 100 hours. The mixture is allowed to stand stillat a temperature of −5° C. to 100° C., preferably 0° C. to 30° C.

A preferred combination of the aforementioned water-soluble organicpolymer (A), the silicate salt (B), and the dispersant (C) for thesilicate salt is, for example, a combination containing the component(A): completely neutralized or partially neutralized linear-chain sodiumpolyacrylate having a weight average molecular weight of 2,500,000 ormore and 5,000,000 or less (0.05% by mass to 10% by mass), the component(B): water-swellable smectite or saponite (0.05% by mass to 10% bymass), and the component (C): sodium pyrophosphate or sodium etidronate(0.5% by mass to 5% by mass) or sodium polyacrylate having a weightaverage molecular weight of 1,000 or more and 20,000 or less (0.5% bymass to 5% by mass).

[Radiation Dosimeter]

The gel dosimeter of the present invention is suitable for a materialfor radiation dosimetry. Thus, the radiation dosimetry gel can becharged into a container and used as a radiation dosimeter, for example,a phantom. No particular limitation is imposed on the container, so longas it is insensitive to MRI, allows radiation to transmit therethrough,and has, for example, solvent resistance and airtightness. Preferredexamples of the material of the container include glass, PET,polyethylene, polypropylene, acrylic resin, polyester, andethylene-vinyl alcohol copolymers. When the container is transparent, athree-dimensional dose distribution can be measured not only with MRI,but also with optical CT capable of three-dimensional measurement ofdegree of clouding. After the container is charged with the gel, theinside of the container may be replaced with, for example, nitrogen gas.

The gel dosimeter of the present invention prepared throughdeoxygenation treatment exhibits superior storage stability at roomtemperature. The gel dosimeter of the present invention exhibits anexcellent deoxygenation effect and superior storage stability at roomtemperature, as compared with a widely used conventional gel dosimetercontaining, as a deoxygenating agent, tetrakis(hydroxymethyl)phosphoniumchloride, sodium ascorbate, copper sulfate, etc. While such aconventional gel dosimeter is inactivated after two weeks of roomtemperature storage, the gel dosimeter provided by the present inventionundergoes no change in X-ray irradiation sensitivity even after twoweeks of room temperature storage.

EXAMPLES

The present invention will next be described in detail by way ofExamples, but the present invention should not be construed as beinglimited to the Examples.

Production Example 1: Production of Aqueous Dispersion of Silicate Salt

14.4 parts of SUMECTON SWF (available from Kunimine Industries Co.,Ltd.) was mixed with 1.5 parts of disodium etidronate hydrate (availablefrom Tokyo Chemical Industry Co., Ltd.) and 84.1 parts of water, and themixture was stirred at 25° C. until a homogeneous aqueous dispersion wasprepared, to thereby produce a target product.

Production Example 2: Production of Aqueous Solution ofHighly-Polymerized Sodium Polyacrylate

4 parts of highly-polymerized sodium polyacrylate (available fromFUJIFILM Wako Pure Chemical Corporation, degree of polymerization:22,000 to 70,000) was mixed with 1.6 parts of magnesium chloridehexahydrate and 94.4 parts by water, and the mixture was stirred at 25°C. until a homogeneous aqueous solution was prepared, to thereby producea target product.

Example 1: Production of Gel Dosimeter Containing Gelatin as Gelator

3 parts of N,N′-methylenebisacrylamide (available from FUJIFILM WakoPure Chemical Corporation), 5 parts of gelatin (available fromSigma-Aldrich), 8 parts of N-vinylpyrrolidone (available from TokyoChemical Industry Co., Ltd.), 1 part of glucose (available from JUNSEICHEMICAL CO., LTD.), and 10 ppm of glucose oxidase (available from TokyoChemical Industry Co., Ltd.) were added to 88 parts of water, and themixture was heated at 45° C. to 50° C. and stirred until homogeneity wasachieved. The resultant mixture was charged into a 15 mL PET container,and then allowed to stand still at 20° C. to 25° C. for 24 hours, tothereby prepare a target product for X-ray irradiation experiment.

Example 2: Production of Gel Dosimeter Containing Water-Soluble OrganicPolymer, Silicate Salt, and Dispersant for Silicate Salt as Gelator

3 parts of N,N′-methylenebisacrylamide (available from FUJIFILM WakoPure Chemical Corporation), 1.5 parts of N,N-dimethylacrylamide(available from Tokyo Chemical Industry Co., Ltd.), 1 part of glucose(available from JUNSEI CHEMICAL CO., LTD.), and 10 ppm of glucoseoxidase (available from Tokyo Chemical Industry Co., Ltd.) were added to66.5 parts of water, and the mixture was stirred at 20° C. to 25° C.until homogeneity was achieved. To the mixture was added 11 parts of theaqueous solution of highly-polymerized sodium polyacrylate produced inProduction Example 2, and the resultant mixture was stirred at 20° C. to25° C. until homogeneity was achieved. To the mixture was added 11 partsof the aqueous dispersion of silicate salt produced in ProductionExample 1, and the resultant mixture was stirred at 20° C. to 25° C. forthree minutes. The resultant mixture was charged into a 15 mL PETcontainer, and then allowed to stand still at 20° C. to 25° C. for 24hours, to thereby prepare a target product for X-ray irradiationexperiment.

Experimental Example 1: X-Ray Irradiation Experiment of Gel Dosimeter

The gel dosimeter sample prepared in Example 1 or Example 2 wasirradiated with X-rays with an X-ray irradiation apparatus (MBR-1520R-4,available from Hitachi Power Solutions Co., Ltd.). Specifically, thesample was irradiated with X-rays at 0.5, 1, 3, 5, or 7 Gy under thefollowing conditions: tube voltage: 150 kV, tube current: 20 mA. Theirradiated sample was analyzed by MRI using 3T MRI (Prisma, availablefrom Siemens). Mixed turbo spin echo sequence was applied as a pulsedmagnetic field for analysis, and the T₂ relaxation time of the samplewas acquired to thereby calculate R₂ (i.e., 1/T₂) and ΔR₂ (taking R₂ ofnon-irradiated sample as 0). FIG. 1 is a graph showing the correlationbetween ΔR₂ and irradiated X-ray dose in Examples 1 and 2. FIG. 2 showsthe state of the dosimeter after X-ray irradiation (Example 1: 0, 0.5,1, 3, 5, and 7 Gy irradiation (from left to right)), and FIG. 3 showsthe state of the dosimeter after X-ray irradiation (Example 2: 0, 0.5,1, 3, 5, and 7 Gy irradiation (from left to right)).

Example 3: Production of Gel Dosimeter Containing Glucose and GlucoseOxidase as Deoxygenating Agent

1.5 parts of N,N′-methylenebisacrylamide (available from FUJIFILM WakoPure Chemical Corporation), 1.5 parts of N,N-dimethylacrylamide(available from Tokyo Chemical Industry Co., Ltd.), 6 parts of4-acryloylmorpholine (available from Tokyo Chemical Industry Co., Ltd.),20 parts of SNOWTEX ST-OXS (available from Nissan Chemical Corporation,solid content concentration: 10%), 1 part of glucose (available fromJUNSEI CHEMICAL CO., LTD.), and 10 ppm of glucose oxidase (availablefrom Tokyo Chemical Industry Co., Ltd.) were added to 70 parts of water,and the mixture was stirred at 20° C. to 25° C. until homogeneity wasachieved. To the mixture was added 11 parts of the aqueous solution ofhighly-polymerized sodium polyacrylate produced in Production Example 2,and the resultant mixture was stirred at 20° C. to 25° C. untilhomogeneity was achieved. To the mixture was added 11 parts of theaqueous dispersion of silicate salt produced in Production Example 1,and the resultant mixture was stirred at 20° C. to 25° C. for threeminutes. The resultant mixture was charged into a mL PET container, andthen allowed to stand still at 20° C. to 25° C. for 24 hours, to therebyprepare a target product for X-ray irradiation experiment.

Production Example 3: Production of Aqueous Dispersion of Silicate Salt

6 parts of LAPONITE XLG (available from BYK Additives & Instruments)were mixed with 1.7 parts of 35% aqueous solution of lowly-polymerizedsodium polyacrylate (average molecular weight: 15,000, available fromSigma-Aldrich), 10 parts of glycerin, parts of citric acid monohydrate,and 81.8 parts of water, and the mixture was stirred with a magneticstirrer at 25° C. until a homogeneous aqueous dispersion was prepared,to thereby produce a target product.

Production Example 4: Production of Aqueous Solution ofHighly-Polymerized Sodium Polyacrylate

2 parts of highly-polymerized sodium polyacrylate (available fromFUJIFILM Wako Pure Chemical Corporation, degree of polymerization:22,000 to 70,000) was mixed with 10 parts of glycerin, 1 part oftrisodium citrate dihydrate, 0.5 parts of citric acid monohydrate, and86.5 parts of water, and the mixture was stirred with a magnetic stirrerat 25° C. until a homogeneous aqueous solution was prepared, to therebyproduce a target product.

Comparative Example 1: Production of Gel Dosimeter ContainingWater-Soluble Organic Polymer, Silicate Salt, and Dispersant forSilicate Salt as Gelator

3 parts of N,N′-methylenebisacrylamide (available from FUJIFILM WakoPure Chemical Corporation), 8 parts of N-vinyl-2-pyrrolidone (availablefrom Tokyo Chemical Industry Co., Ltd.), and 200 ppm of hydroquinonewere added to 65.8 parts of water, and the mixture was stirred at 20° C.to 25° C. until homogeneity was achieved. To the mixture were added 11parts of the aqueous solution of highly-polymerized sodium polyacrylateproduced in Production Example 4, and 1.2 parts (corresponding to 50 mM)of 80% aqueous solution of tetrakis(hydroxymethyl)-phosphonium chloride(available from Tokyo Chemical Industry Co., Ltd.), and the resultantmixture was stirred. The mixture was cooled to 5° C. or lower, and then11 parts of the aqueous dispersion of silicate salt produced inProduction Example 3 was added to the mixture, followed by stirring forone minute. The resultant mixture was charged into a 30 mL PETcontainer, and then allowed to stand still at 20° C. to 25° C. for 24hours, to thereby prepare a target product for X-ray irradiationexperiment.

Experimental Example 2: Room Temperature Storage Experiment

Target products prepared in Example 3 and Comparative Example 1 wereirradiated with X-rays in the same manner as in Experimental Example 1one day after preparation of the products. Separately prepared targetproducts of Example 3 and Comparative Example 1 were allowed to standstill in a room at a temperature of 23° C. to 25° C. for two weeks, andthen the target products were irradiated with X-rays in the same manneras in Experimental Example 1. Each of the irradiated samples wasanalyzed in the same manner as in Experimental Example 1, to therebycalculate ΔR₂. FIG. 4 is a graph showing the correlation between ΔR₂ andirradiated X-ray dose in Example 3 after one day and after two weeks.FIG. 5 is a graph showing the correlation between ΔR₂ and irradiatedX-ray dose in Comparative Example 1 after one day and after two weeks.As indicated by the comparison between the results shown in FIG. 4 andFIG. 5 , a conventional gel dosimeter containingtetrakis(hydroxymethyl)phosphonium chloride as a deoxygenating agent wasalmost completely inactivated after two weeks of room temperaturestorage, whereas the gel dosimeter of the present invention containingglucose and glucose oxidase as a deoxygenating agent underwent no changein X-ray irradiation sensitivity even after two weeks of roomtemperature storage. Thus, the gel dosimeter of the present inventionwas found to exhibit superior room temperature storage stability.

INDUSTRIAL APPLICABILITY

The gel dosimeter of the present invention for a radiation dosimeter canbe readily produced from industrially easily available raw materials,and exhibits excellent irradiation sensitivity, linearity, and storagestability. Thus, the gel dosimeter can be applied to various radiationtherapies.

1. A gel dosimeter for radiation dosimetry comprising a radicallypolymerizable monomer, a gelator, glucose, and glucose oxidase.
 2. Thegel dosimeter for radiation dosimetry according to claim 1, wherein thegelator is one or more selected from the group consisting of gelatin,agarose, xanthan gum, carrageenan, gellan gum, chitosan, and alginicacid, and sodium, potassium, magnesium, and calcium salts thereof,including partially neutralized products thereof.
 3. The gel dosimeterfor radiation dosimetry according to claim 1, wherein the gelatorcontains polyvinyl alcohol and glutaraldehyde or borax.
 4. The geldosimeter for radiation dosimetry according to claim 1, wherein thegelator contains a water-soluble organic polymer (A) having an organicacid structure, an organic acid salt structure, or an organic acid anionstructure, a silicate salt (B), and a dispersant (C) for the silicatesalt.
 5. The gel dosimeter for radiation dosimetry according to claim 4,wherein the water-soluble organic polymer (A) is a completelyneutralized or partially neutralized polyacrylic acid salt having aweight average molecular weight of 1,000,000 to or a mixture thereof. 6.The gel dosimeter for radiation dosimetry according to claim 4, whereinthe silicate salt (B) is one or more water-swellable silicate saltsselected from the group consisting of smectite, bentonite, vermiculite,and mica.
 7. The gel dosimeter for radiation dosimetry according toclaim 4, wherein the dispersant (C) is one or more selected from thegroup consisting of sodium orthophosphate, sodium pyrophosphate, sodiumtripolyphosphate, sodium tetraphosphate, sodium hexametaphosphate,sodium polyphosphate, sodium etidronate, sodium poly(meth)acrylate,ammonium poly(meth)acrylate, a sodium acrylate/sodium maleate copolymer,an ammonium acrylate/ammonium maleate copolymer, sodium hydroxide,hydroxylamine, sodium carbonate, sodium silicate, polyethylene glycol,polypropylene glycol, sodium humate, sodium ligninsulfonate, andpotassium salts corresponding to these salts.
 8. The gel dosimeter forradiation dosimetry according to claim 1, wherein the radicallypolymerizable monomer is a water-soluble polymerizable monomer.
 9. Thegel dosimeter for radiation dosimetry according to claim 1, wherein thegel dosimeter further comprises a water-soluble polyfunctionalacrylamide monomer as a crosslinking agent.
 10. The gel dosimeter forradiation dosimetry according to claim 1, wherein the gel dosimeterfurther comprises water-dispersible inorganic microparticles as asensitizer.
 11. The gel dosimeter for radiation dosimetry according toclaim 1, wherein the gel dosimeter further comprises, as a stabilizer, apolymerization inhibitor, a radical scavenger, or an antioxidant. 12.The gel dosimeter for radiation dosimetry according to claim 1, whereinthe gel dosimeter further comprises a buffer.
 13. The gel dosimeter forradiation dosimetry according to claim 12, wherein the buffer is one ormore selected from the group consisting of phosphoric acid, citric acid,acetic acid, boric acid, tartaric acid, salts of these, Tris, and HEPES.